Arynes are a privileged class of reactive intermediates in synthetic organic chemistry, and their unusual reactivities have been the subject of engrossing research interest. Recently, there are many reports on novel aryne-based synthetic innovations as a linchpin approach to accomplish the total synthesis of structurally diverse natural products or their derivatives in a racemic and enantiopure fashion. This review provides an overview of the literature on synthetic strategies, employing arynes as crucial intermediates to construct architecturally intriguing bioactive natural products/derivatives in a period of 2019 to 2022. This study highlights the need to investigate the effective synthesis and search for new biological uses of highly functionalized natural product skeletons.